Substituted guanidine alcohols



Patented May 19, 1931 UNIT STATES PATENT OFFICE WALTER SCHOELLER AND SCHOTTE', OF BERLIN, GERMALIY, ASSIGNORS TO THE FIRM SHERING-KAHLBAUM AKTIENGESELLSCHAFT, OF BERLIN, GERMANY SUBSTITUTED euenimnniinoonons No Drawing. Application filed June 21, 1926, SerialNo. 117,569, andin'Germ'any January 7, 1925.

Our invention refers to new chemical com-. pounds, viz. substituted guanidines, and to the method of producing same. This method consists in causing S-alkyl isothiourea or its derivatives to act on a solid or liquid amine orits derivatives having a basic reaction and which are liquid or solid at ordinary temperature, with or without the use of solvents. The reaction results in the splitting off of a mercaptan and the production of the corresponding guanidine compound. The corre sponding amine need not be used in great excess, 1 to 1 molecules of amine at the utmost sufiicing for quantitative reaction.

The new compounds have the general formula wherein R is a hydrogenatom, univalent hydrocarbon radical or an acyl group and the two Rs may be the sameorjdiiierent, while I X is a hydroxylated or alkoxylated alkyl group and Y a hydrogenatom or an alkyl group or X and Y form together a carbocyclic system, these products being bases capable of forming salts with acids and being decomposed by concentrated alkali.

The novel compounds are designed for therapeutical uses. They are decomposed by alkaline compounds and can be combined with phosphor-tungstic acid into complex compounds.

Example 1 The residue sometimes solidifies into Thelpicrate remains oily and dissolves with relative facility in, water. The reaction 00- curs according to the formula I CH -OH2OH N 2 185 grams S-ethyl isothiourea hydrobromide are dissolved in 40 ccms of water and 105 grams of O-acetyl amino ethanol are added. The mixture is allowed to stand some time and soon the reaction sets in, which results in about the equivalent quantity of mercaptan being liberated which is removed HBr ,Eaeaoiple 3 p 185 grams of S-etl1yl isothiourea hydrobromide and 77.5 grams of methyl amino ethanol are mixed, if desired in the presence of water. If this mixture is treated as usual the hydrobromide will crystallize'out directly. It is also possible'to, precipitate the picrate of methyl guanidine ethanol which melts at 162-16 1 and dissolves withdifiiculty in cold water, but very easily in hot water. By decomposing the picrate with hydrochloric acidand extracting the picric v acid with ether there. is obtained the solution of the hydrochloride which on concentration.

In consequence of its formation this compound has an asymmetric structure. It represents the alcohol of creatin, which hitherto could not be obtained, of the formula cit-omen N CH3 T=NH H N H Instead of 185 grams of S-ethyl isothiourea hydrobromide 21 1 grams of S-methyl isothiourea hydroiodide can be caused to act 01177.5 grams methyl ammo ethanol. The

compound thus obtained is identical with.

the one above described. The picrate melts at 166, the hydrochlorideat 7 8, the hydrobromide at 103, the picrolonate is decomposed at 236237.

Example 4 185 grams of 'S-ethyl isothiourea hydrobromide are dlssolved in a small quant ty of water and are caused to react under formation of mercap'tan with 120 grams of O- acetyl methyl amino ethanol. The product of reaction having the formula as well as its picrate were obtained in the form of an 011.

E wample 5 A mixture of equimolecular quantities of ethyl amino ethanol and S-methyl isothiourea hydroiodide will react to form ethyl guanidine ethanol having the formula The picrate melts at 158. The hydrochloride forms hydroscopic crystals.

E mample 6 In the same manner as described with reference to Example 5 there is obtained the iso amyl. homologue the picrat'e of which melts at 117 118", while the hydrochloride forms a radiated crystal-v line mass.

' 7 Example '7 1 grams of N-methyl-S-ethyl isothiourea hydrobromide, if mixed with 8 grams of methyl amino ethanol react to form N- methyl-N'-methyl hydroXy ethyl guanidine The picrate and the picrolonate of this compound dissolve in water only with difficulty While the hydrochloride, bromide, and iodide dissolve readily.

Emample 8 15 grams of amino acetal, if mixed with a solution of 18 grams of S-ethyl isothiou'rea hydrobromide in 4 ccms of water, react after a few minutes. The mixture is allowed to stand over-night, when the mercaptan and the water are removed by distillation. There remains the. guanidine acetyl hydrobromide, which melts at 5354 and is hydroscopic,

while the hydroiodide which is obtained from S-methyl isothiourea hydroiodide, melts at about and the picrate at 201. The product of reaction proper has the formula H I cmo11 oo2mn HBr E mample 9 3 parts of methyl amino acetal and 3.7 parts of S-ethyl isothiourea hydrobromide react quantitatively under the formation of N methyl N (,B-dioxe'thyl) ethyl guanidine hydrobromide.

HBr

The picrate soluble only with difficulty and melts, at 116.

E mample' 10 19 grams of S-ethyl-N-methyl isothiourea hydrobromide-are moistened with a little water and on addition of 13 grams of amino acetal result in a colorless syrup, from which canbeprecipitatedthepicrate ofN-methyl-N- B-dioxethyl) ethyl guanidine to stand overnight at about or is heated during 5 hours to 801 O0. During the heating large quantities of mercaptan are developed. The last traces of mercaptan and unchanged aniline are extracted with ether. The residue is phenyl guanidine having the form of a slightly yellow-colored syrup. Its picrate dissolves only with difficulty and melts at 223, the hydrobromide melts at 71.

Ema-mple12 By reacting with IO'grams of u-amino pyridine on 18 grams of S-ethyl isothiourea hydrobromide there is obtained alpha-guanyl-2-pyridinehydrobromide being a thick, somewhat brownish syrup which readily dissolves in solvents contain-. ing the hydroxyl group.

v Example 13 v v 10 grams of piperidine react under vigorous evolution of heat with mole S-ethyl 1 isothiourea hydrochloride. The resulting alpha-guanyl-l-piperidine hydrochloride CHr-CH CHz-CHZ no] =NH 1 11512 melts at 166, the hydrobromide at about 1 the picrate at 248.

E wample 14 To 12 grams of p-amino phenol are added 100 ccms of alcohol and a solution of 18 grams of S-ethyl isothiourea hydrobromide in 4 ccms of water. On being allowed to stand at about 40 for a longer time all the phenol dissolves and a great quantity of mercaptan forms. The guanidine phenol hydrobromide is a microcrystalline powder soluble in water. The picrate melts at 2289.

Example 15 The product obtained by reacting with 22 grams of 4-amino-l-phenyl-2.3-dimethyl-5- pyrazolon on 18 grams of S-ethyl isothiourea hydrobromide is readily soluble in water;

It has the formula NE E o N-oro Emamp'lel" 6.4 parts of phenyl hydrazine react vigorously with 11 parts of S-ethyl isothiourea hydrobromide under formation of phe-nyl amino guanidine hydrobromide I which crystallizes at once and melts at 196.

HBr

The picrate dissolves in water only with difliat 199. Example 1 7" 21 grams of pyrrolidine and 54.6 grams of S-ethyl isothiourea hydrobromide react under formation of guanyl pyrrolidine hydrobromide I culty and melts CH2YJCHQ CH1 CH2 NHz-ON v r I Its picrate dissolves only with .dilficulty in water and melts at 211 The salts of the hydro- HDr chloride bromide and iodideare readily sol'uble in water.

Emample l is almost pure enough to be analysed. It is scarcely soluble in water, only with difficulty in alcohol and acetone, readily dissolves in hot acetic ester and melts at 181.

Example 19 V I 250 grams of 1.3-dicarbethoXy-2-ethyl isothiourea are allowed to stand some time at ordinary temperature with about an equal quantity of benzyl amine. The mercaptan and the excess of amine are removed by distillation in Vacuo and the residue forms alphareadily soluble in organic solvents.

Emample 20 grams 1.3 dibenzoyl-2-ethy1 isothiourea, if caused to react as above described, with methyl amino ethanol form the creatinol dibenzoate (alpha-beta-di-benzoyl gammamethyl-hydroxy ethyl guanidine) on3 /1\!TCH2CH20H o=Noo-ou15 NHco-oun which is insoluble in water and petroleum ether and dissolves only with difiiculty in alcohol.

Ewample 21 The same compound is obtained if methyl amino ethanol is allowed to act on 1.3-di benzoyl-2-methyl isothiourea. Here is formed the methyl mercaptan. The yield is Allthe above temperatures are given in degrees centigrade.

Various changes may be made in the details of the operation and particularly in the proportions of the ingredients present in the solutions used without departing from the invention or sacrificing the advantages thereof.

In the appended claims the terms S-alkyl isothiourea and amine are meant to cover also the derivatives.

We claim 1. As a new product the alcohol of creatin having the formula 2. As a new product a substituted guanidine having the formula:

'- whereinR is a hydrogen atom, univalent hy- N (CH2) n CH2OH wherein R is a hydrogen atom, univalent hydrocarbon radical, or an acyl group and the three Rs may be the same or different, while 01, is a whole number, these products being bases capable of forming salts with-acids and being decomposed by concentrated alkali.

4:. The method of producing substituted guanidine comprising causing an S-alkyl isothiourea to act on a non-gaseous monoamine having at least one hydrogen atom attached to the nitrogen atom.

5. The method of producing substituted guanidine comprising causing an S-alkyl isothiourea to act in the presence of a solvent on a non-gaseous monoamine having at least one hydrogen atom attached to the nitrogen atom.

In testimony whereof we aflix our signa- 

